Fluoxetine as shown below in Formula I ##STR1## in the form of hydrochloride salt is used as an efficient antidepressant drug. Its pharmacological activity is attributed to its ability to be a potent and selective serotonin re-uptake inhibitor.
Fluoxetine and a process for the preparation of fluoxetine and its pharmaceutically acceptable addition salts were described in U.S. Pat. No. 4,314,081 and U.S. Pat. No. 4,194,004 respectively and U.S. Pat. No. 4,018,895 describes its use in treating depression. In all these patents the same preparation process was described.
In that process 3-dimethylamino propiophenone (formula II) is liberated from its hydrochloride salt and reduced with diborane to yield 3-dimethylamino-1-phenyl-1-propanol (formula III) ##STR2##
The compound of formula III is treated with HCl and thionyl chloride to yield the chloro derivative (formula IV) ##STR3## which is then refluxed under alkaline conditions with 4-trifluoromethyl phenol (formula V) for five days ##STR4## to yield N,N-dimethyl-3-[4-(trifluoromethyl)phenoxy]-3-phenyl propylamine (formula VI) ##STR5##
Finally the compound of formula VI is demethylated in a two-step reaction: In a first step the compound is reacted with cyanogen bromide and in a second step with a mixture of KOH/ethylene glycol for 20 hours at 130.degree. C. The crude fluoxetine thus obtained is precipitated as the oxalate or maleate salt.
This process suffers from several disadvantages, the most important of which are:
a) Low overall yields; the yield from compound II to fluoxetine oxalate being only about 32%. PA1 b) The substituted phenol (formula V) which is an essential building block, is not available commercially. PA1 c) The cyanogen bromide which is used in this process is highly toxic. PA1 d) Long time and extreme reaction conditions are required in both the reaction of the compound of formula IV with the compound of formula V and in the demethylation of the compound of formula VI to yield fluoxetine. PA1 a) The fluoxetine thus obtained is so impure that is has to be purified by preparative HPLC. This is a very costly technique and almost impossible to carry out on a commercial production scale. PA1 b) The process yields phenol in the aqueous waste withdrawn from the demethylation reaction of the compound of formula VI which is a major ecological problem.
Several years later Robertson et al., J. Labelled Compd. Radiopharm., 24, 1997 (1987) described a related process which overcomes some of the above drawbacks. In this process the compound of formula III is directly coupled with the commercially available 4-chlorobenzotrifluoride (formula VII) ##STR6## to yield the compound of formula VI. Another change consists in thatcyanogen bromide is replaced by the less toxic phenyl chloroformate which, moreover, also reduces the reaction time and temperature of the demethylation of the compound of formula VI.
This process has, however, other disadvantages:
Several more processes are described in the literature, but they all suffer from significant drawbacks such as the necessity of catalytic reductions or catalytic dehydrogenations as in the process described, for example, in EP 391,070. EP 380,924 involves a difficult reduction step which is performed using the relatively expensive and dangerous agent (LiAlH.sub.4). Another process is described by Srebnik et al. J. Org. Chem., 53, 2916 (1987), but has the disadvantage that it requires high pressure reactions.